DE3918015A1 - METHOD FOR THE PRODUCTION OF MUSCON, INTERMEDIATE PRODUCTS FOR THIS METHOD AND THE PRODUCTION THEREOF - Google Patents

Description

The present invention relates to a method for producing the desired Fragrance Muscon by intramolecular aldol condensation of Hexadecane-2,15-dione or hexadecadiene-2,15-dione in the gas phase as well new hexadecadiene-2,15-diones and an advantageous process for their Manufacturing.

Muscon (3-methyl-cyclopentadecanone) of the formula I.

is one of the most important ingredients of the very popular in perfumery natural musk extracts. As a result of the extremely high price for natural extracts, the synthetic production of I is of great Interest, especially since I all other known musk fragrances, such as the tetralin or nitromusus compounds, is far superior.

The manufacturing methods used so far are mainly based on Ring expansion reactions based on cyclododecanone (cf. for example Helv. Chim. Acta, 71 [1988], pp. 1704-1718, and in loc. cit. named Literature). These methods all have partially very complex multi-stage Procedural steps and are therefore economical Use unattractive.

Other known synthetic methods involve intramolecular condensation reactions such as aldol, Dieckmann or acyloin condensation (see also Houben-Weyl, Methods of Organic Chemistry, Vol. 4/2, pp. 729-815). These methods all have the major disadvantage that they can only be diluted at very high levels relatively good yields of macrocycles can be obtained.

In Helv. Chim. Acta, 62 (1979), pages 2673-2680, is a novel Synthesis method for Muscon based on 4,8-dodecadiene diol presented. The key step here is the acid-catalyzed intramolecular cyclization an open-chain hydroxyacetal to form bicyclic dihydropyran, however, due to the necessary dilution principle, high amounts of solvent are required, making this procedure only for the Synthesis of laboratory quantities is useful.  

It seemed like a pretty good option for making I for the first time by Stoll (cf. Helv. Chim. Acta, 30 [1947], pages 2019-2023) Aldol condensation described starting from hexadecane-2,15-dione To be Formula IIa

since the methyl group in the 3-position of I is also introduced here becomes.

However, this process had considerable disadvantages:

• 1) Were the manufacturing options for what was needed as the starting material Ketone of the formula IIa or of adequate 2,15-diketones has so far been unsatisfactory.
• 2) Are the yields to be achieved in the aldol condensation despite the Working in highly diluted solutions relatively low (according to loc. Cit. 17%).

To 1:
There has been no shortage of attempts in the past to develop suitable manufacturing options for IIa. Stoll synthesized it according to the following reaction scheme:

The disadvantage of this synthesis is in particular the use of the expensive one and also toxicologically questionable 1,10-dibromodecans.

Furthermore, in J. Am. Chem. Soc., 82 (1960), pages 1447-1450, the the following synthesis based on 2,2 ′, 5 ′, 2 ′ ′ - terthienyl is presented:

For the synthesis of larger amounts of diketone, however, this synthesis is due to the poor accessibility of the starting material is not suitable.

Two further processes for the production of diketone IIa each starting out of butadiene have been described by Tsuji et al. described:

• a) in Chem. Lett., 1976, pages 773-774: and
• b) in Bull. Chem. Soc. Japan, 51 (1978), page 1915:

Expensive palladium catalysts are used in both processes, which also makes this synthesis unattractive for industrial use will.

Furthermore, from Bull. Chem. Soc. Japan, 56 (1983), pages 345-346, a process for the preparation of IIa starting from α, ω- tetradecanedicarboxylic acid is known. A disadvantage of this method is the poor accessibility of the starting compound.

From J. Organomet. Chem. 264 (1984), pages 229-37, is also a process for the production of IIa starting from (CH₃) ₃Si-CH₂-CH = CH-CH₂-CH₂-C (CH₃) = CH-CH₂-Si (CH₃) ₃ known. Disadvantageous This method is in addition to the poor accessibility of the starting compound the need to use problematic Reagents such as the highly flammable potassium hydride.

It was therefore an object of the invention to be technically simple and Find cheap manufacturing methods for the hexadecane-2,15-dione.

This task was accomplished by providing the new double unsaturated 2,15-diketones of the general formula II

CH₃-CO-X-CO-CH₃ (II)

in the X for an unbranched alkadienylene radical of the structure

stands,
essentially solved, since these 2,15-diketones can be produced on the one hand in a technically simple manner and on the other hand can be converted very advantageously into the diketone IIa and into Muscon.

The invention therefore also relates to a method for the production a mixture of the 2-unsaturated 2,15-diketones of the formulas IIb and IIc

which is characterized in that 1,10-decanediol of the formula III

oxidatively dehydrated,
the 1,10-decanedial of formula IV thus obtained

a Wittig reaction with 2 moles of a 2-oxo-propenyl-triphenylphosphonium salt Formula V

wherein
Y⊖ stands for Cl⁻, Br⁻ or HSO₄⊖, subjects and distills the reaction product.

The 1,10-decanediol required for this process is commercially available Compound created by alkaline splitting of castor oil and subsequent Hydrogenation of the sebacic acid obtained in a relatively simple manner can be.

The oxidative dehydrogenation of the 1,10-decanediol in the 1,10-decanediol can can be realized in different ways. One works with advantage in the Gas phase on silver catalysts, such as in Manuf. Chem. Aerosol News, 37 (1966), pages 42-45, for C₅-C₁₄ alcohols. Closer Details of the reaction conditions for this stage of the process can be found in the cited reference. But it can also by oxidation in methylene chloride with aqueous NaOCl solution in the presence of catalytic amounts of 4-methoxy-2,2,6,6-tetramethyl-piperidine-N- oxide. For more details on this stage of the process we refer to J. Org. Chem., 52 (1987), pages 2559-2562.

To carry out the Wittig reaction with a 2-oxypropenyl triphenyl phosphonium salt of formula V is advantageously carried out in such a way that the triphenylphosphonium salt in an inert organic solvent, such as Methylene chloride and the solution of the 1,10-dial in one inert, preferably slowly adding the same inert solvent and the reaction mixture is stirred for a further 1 to 2 hours.

The work-up is carried out in a manner customary for Wittig reactions Concentration, precipitation of the phosphine oxide and distillation. By 13 C NMR Investigations showed that the distillative workup of the Reaction mixture a part of the diketone initially formed Formula IIb isomerized to the diketone of Formula IIc.

The invention also relates to a method for producing the double unsaturated 2,15-diketone of the formula IId

which is characterized in that one  

• A. 1,6-hexane diol of formula VI oxidatively dehydrated,
• B. the resulting adipindialdehyde of formula VII with 2 mol of a vinyl magnesium halide of the formula VIIICH₂ = CH-Mg-Hal (VIII) in which Hal is Cl or Br, reacted in a Grignard reaction and
• C. the 1,9-decadiene-3,8-diol of the formula IX obtained in this way

a Carroll reaction with an alkyl acetoacetate.

The 1,6-hexane-diol required for this process is on an industrial scale available and therefore cheap exit connection.

The oxidative dehydrogenation of 1,6-hexanediol to adipindialdehyde can for example analogous to the oxidative dehydrogenation described above of 1,10-decanediol in the gas phase on a silver catalyst or with aqueous NaOCl solution in the presence of 4-methoxy-2,2,6,6-tetramethylpiperidine N-oxide.

The subsequent vinylation is carried out with 2 mol of a vinyl magnesium salt in the usual way for Grignard reactions. For example, the vinyl magnesium halide is made in a solvent such as tetrahydrofuran (THF) and submitted and for this purpose slowly and under temperature control a solution of adipindialdehyde in THF was added. Through usual workup and fractional distillation gives the 1,9-decadiene 3,8-diol of formula IX in very good yields. For more details of this reaction step we refer to Bull. Soc. Chim. France, 1959, pages 1248-1251, esp. 1248.  

The Carroll reaction of 1,9-decadiene-3,8-diol with an alkyl acetoacetate, preferably with methyl acetoacetate by slow Heat both reactants to temperatures of around 200 ° C. The cleavage of methanol begins at about 160 ° C. and then the elimination of CO₂.

For further details of the Carroll reaction, ie the addition of α, β- unsaturated alcohols to compounds with an active methylene group, reference is made to Chem. Soc. Chim. France, 1940, pages 704-706.

The double unsaturated 2,15-diketones of the formulas IIb to IId can like the already known Diketon IIe in a simple manner and in good yields, for example by catalytic hydrogenation on one Palladium catalyst, in the saturated 2,15-hexadecanedione of formula IIa be transferred.

To 2:

It has been found that the intramolecular aldol condensation of 2,15-hexadecanedione of the formula IIa yields of up to 60% of theory can be obtained if this aldol condensation is not - as is known - in highly diluted solution, but at temperatures from 300 to 450 ° C and in Presence of small amounts of water in the gas phase on a fixed bed catalyst containing as a catalytically active compound TiO₂, CeO₂ or ThO₂, preferably TiO₂, is carried out. It was very surprising that this long-studied and sensitive implementation under the drastic conditions a gas phase reaction is extremely advantageous.

It was already a gas phase cyclization reaction, namely cyclization known from dimethyl octandecanedioate to cycloheptadecanone, however, the desired cyclization product was only obtained in yields obtained from 14% of theory (determined by gas chromatography) (cf. Parfumer and Flavorist, Vol. 7 [1982], page 57). The main product of this Cyclization reaction was polymeric material.

Surprisingly, it was also found that the double unsaturated 2,15-diketones of the formulas IIb to IIe in the gas phase Catalysts containing as a catalytically active compound TiO₂, CeO₂ or ThO₂ can be cyclized with good yields.

This was particularly surprising since J. Organometallic Chem., 264 (1984), Pages 229-237, especially 234, was known that in an attempt to 2,15-diketone of the formula IIe in the known manner with diisobutylaluminum hydride,  To cyclize phenol and pyridine only yields of about 6% of theory can be achieved on the corresponding cyclic ketone could.

The invention therefore relates in particular to a method for Preparation of Muscon of Formula I.

which is characterized in that open-chain 2,15-diketones of general formula II

CH₃-CO-X-CO-CH₃ (II)

in the X for one of the remnants

stands,
at temperatures of 300 to 400 ° C, preferably 350 to 380 ° C, in the presence of 5 to 15 wt .-% water, based on the amount of catalyst, in the gas phase over a fixed bed catalyst containing as a catalytically active compound TiO₂, CeO₂ or ThO₂, preferably brings a TiO₂ catalyst into contact and the unsaturated cyclic ketone which forms here by intramolecular aldol condensation is catalytically hydrogenated.

The aldol condensation according to the invention is particularly advantageous. if the 2,15-diketones of the general formula II with a Alkali or alkaline earth metal oxide doped TiO₂ catalyst in contact brings.

Since the 2,15-diketones of the general formula II according to those described above Have the process produced in a technically simple manner, This results in a technically simple and advantageous synthetic route the popular musk fragrance muscon.  

The intramolecular aldol condensation is in the gas phase at one temperature from 300 to 400 ° C, preferably 350 to 390 ° C, especially 350 up to 380 ° C. As catalysts for the process according to the invention is used with particular advantage TiO₂, especially with alkali or alkaline earth metal oxides doped TiO₂, d. H. about 2 to 10 wt .-% Na₂O and / or K₂O containing TiO₂. The catalysts described can for example in the form of 2 to 4 mm strands or in the form of tablets with a diameter of 3 to 4 mm. When implementing in the In the gas phase, it is advisable to maintain a catalyst load of 0.1 to 30 g, in particular 1 to 10 g, open-chain diketone of the formula II per g of catalyst and hour on.

In general, a solution is initially used to carry out the implementation the crystalline diketones of formula II in an inert organic Solvents such as toluene or a xylene in a tubular reactor evaporates and then - optionally together with an inert gas such as carbon dioxide or nitrogen - gaseous at the desired reaction temperature passed over the fixed catalyst. For good yields To achieve cyclic ketone is still the addition of low Amounts of water necessary to coke the catalyst prevent. It is advantageous to work with 5 to 15% by weight of water, based on on the amount of catalyst.

The reaction products are condensed by means of suitable cooling devices and examined by gas chromatography. Reaction products with unreacted Starting material can be re-created without Return further purification directly to the cyclization reaction.

The unsaturated cyclic obtained in this aldol condensation Ketones of the formulas Xa to Xc

are then in a conventional manner by hydrogenation in the presence of Pd catalysts in the desired musk fragrance Muscon transferred.  

With the help of the intramolecular aldol condensation according to the invention 2,15-diketones of the formula II and the subsequent catalytic hydrogenation the popular musk fragrance Muscon can be used in excellent yields be preserved. By providing the new 2.15 diketones of the formulas IIb to IId and advantageous processes for their production result thus a technically simple and advantageous synthesis route of good accessible raw materials for the coveted Muscon.

Example 1 a) Preparation of adipindialdehyde (VII)

In a 4-liter three-necked flask at room temperature (RT) submitted the following chemicals:

59 g (0.5 mol) 1,6-hexanediol,
3.9 g (0.025 mol) of 2,2,6,6-tetramethyl-piperidine-1-oxide,
3.0 g (0.025 mol) KBr,
7.8 g (0.05 mol) NaH₂PO₄ × 2 H₂O,
8.9 g (0.05 mol) NaH₂PO₄ × 2 H₂O,
1 l CH₂Cl₂ + 375 ml water.

567 g (0.51 mol) of one were then added within 2 hours (h) 13% aqueous NaOCl solution added dropwise (slightly exothermic). Here the pH of the reaction solution changed from 6.7 to 6.0. To the dropping was stirred for 15 minutes (min) at RT. After this The organic phase was separated off twice with each 200 ml of CH₂Cl₂ extracted, the combined organic phases with NaHCO₃ solution washed neutral and dried with Na₂SO₄. After this Filtering off Na₂SO₄ was the solvent on a rotary evaporator distilled off and a gas chromatogram was taken from the residue.

The crude product was vinylated directly in the next step.

b) Preparation of 1,9-decadiene-3,8-diol (IX)

0.81 l of a 1.55 molar vinyl magnesium chloride solution in tetrahydrofuran (THF) were submitted. 48.0 g of adipine dialdehyde were obtained within 1 h (raw, 80.5%), dissolved in 50 ml THF, under temperature control added dropwise and then stirred for 2 h. According to the usual Work-up remained 59.6 g of a light yellow oil, the under strong reduced pressure (oil pump) was fractionally distilled.  

The yield after distillation (bp. 0.5 = 108 to 110 ° C) was 36.4 g (91%), corresponding to a yield of 64% of theory.

c) Preparation of 5,11-hexadecadiene-2,15-dione (IId)

A mixture of 36.4 g of a 91% (corresponding to 0.19 mol) 1,9-decadiene-3,8-diols and 74.5 g (0.61 mol) methyl acetoacetate was heated to 200 ° C within 3 h. The started at approx. 160 ° C Elimination of methanol, then the elimination of CO₂. A total of 14.1 g of low boiler distilled (bp. <70 ° C), and there were 9.5 l Split off CO₂ (theory 10.2 l). The residue (73.5 g) was then fractionating under greatly reduced pressure (oil pump) distilled.

The yield after distillation (bp. 0.5 = 160 to 170 ° C.) was 38.6 g (81%), corresponding to a yield of 66% of theory.
Melting point 54 ° C.

1 H-NMR (CDCl₃): δ = 1.32 (4 H, m); 1.8-2.0 (4H, m); 2.1 (6H, s); 2.2-2.3 (4H, m); 2.5 (4H, b); 5.3-5.4 (4H, m); 13 C-NMR (CDCl₃): δ = 26.9; 28.9; 29.6; 32.3; 43.6; 128.6; 131.3; 207.4.

d) Preparation of hexadecane-2,15-dione

38 g of hexadecane-5,11-diene-2,15-dione (0.152 mol) were in 200 ml of ethyl acetate dissolved and at 50 ° C under standard conditions 1.9 g of 10% Pd / C hydrogenated. It was obtained after recrystallization Petroleum ether 25.8 g of a 97% hexadecane-2,15-dione with a Melting point of 80 ° C. The yield was thus 66% of theory.

Example 2 a) Preparation of 1,10-decandial (IV)

37 g (0.2 mol) of 1.10- Decanediol converted to 1,10-decanedial by oxidation. Yield: 31 g (79%) corresponding to 73% of theory.  

b) Preparation of 3,13-hexadecadiene-2,15-dione (IIb) and 5,11-hexadecadiene-2,15-dione (IIc)

1150 ml of a 0.783 molar solution of triphenylphosphine-2-oxo propylene in dichloromethane (0.9 mol) were placed at RT. To that obtained Wittig reagent was a solution of within 2 h 69.5 g of 1,10-decanedial (0.33 mol) in 250 ml of dichloromethane were added dropwise (slightly exothermic reaction) and stirred for another hour. To Working up the contents of the flask were concentrated and the residue with 1 l cyclohexane stirred. The crystallized phosphine oxide was filtered off and the mother liquor again with 300 ml of cold cyclohexane touched. After the residual amount of phosphine oxide had been separated off, the Mother liquor concentrated and under reduced pressure (oil pump) fractionally distilled.

The yield of 3,13-hexadecadiene-2,15-dione was 72 g (93%) from Bp .: 136-139 ° C / 0.03 mm, corresponding to a yield of 81% of Theory.

13 C-NMR (CDCl₃): δ = 197.4 (C-2, C-15); 147.6 (C-4, C-13); 131.4 (C-3, C-14); 32.3 (C-5, C-12); 29.2 (C-8, C-9); 29.1 (C-7, C-10); 28.2 (C-6, C-11); 26.7 (C-1, C-16).

The evaluation of the 13 C-NMR data of the reaction products showed that at the distillation 25% of the compound of formula IIb obtained in the Compound of formula IIc are isomerized.

13 C-NMR (CDCl₃): δ = 206.0 (C-2, C-15); 134.9 (C-5); 122.3 (C-4); 47.5 (C-3); 32.4 (C-6); 28.6 (C-7).

Examples 3 to 8

In each case a solution of 1.5 g of a hexadecane obtained according to Example 1 2,15-dions (IIa) in a mixture of 20 ml decalin and 10 ml toluene was evaporated in a tubular reactor and then added together with nitrogen the reaction temperature specified in the table in gaseous form via a a column (d = 22 mm; length = 50 cm) fixed catalyst composition shown in the table in the form of 2 to 4 mm Strands headed. In Examples 1 to 4, the reaction mixture also add the amount of water shown in the table.

The reaction products were by means of a suitable cooling device condensed, then examined by gas chromatography and then in Hydrogenated in the presence of Pd catalysts.

The reaction conditions and the test results achieved are in compiled in the following table.

table

Example 9

A solution of 4.5 g of a prepared analogously to Example Ia to c 5,11-hexadecadiene-2,15-dione IId in 20 ml toluene per hour (LHSV = 0.03) was evaporated with the addition of 5 ml of water / h in a tubular reactor and together with 10 L N₂ / h and at 380 ° C gaseous over one in a column (d = 22 mm; l = 50 cm) fixed catalyst consisting of TiO₂ and 2% Na₂O in the form of 2 to 4 mm strands. The reaction products were condensed using a suitable cooling device and then examined by gas chromatography.

A selectivity of hexadehydromuscon was obtained with a conversion of 66% of 63% of theory.

Claims (10)

1. Process for the preparation of muscon of the formula I. characterized in that open-chain 2,15-diketones of the general formula IICH₃-CO-X-CO-CH₃ (II) in the X for one of the radicals stands,
at temperatures of 300 to 400 ° C in the presence of 5 to 15 wt .-% water, based on the amount of catalyst, in the gas phase on a fixed bed catalyst containing as a catalytically active compound TiO₂, CeO₂ or ThO₂ in contact, and this thereby Intramolecular aldol condensation forming unsaturated cyclic ketone catalytically hydrogenated. 2. A process for the production of muscon according to claim 1, characterized in that that the 2,15-diketones of the general formula II Bring temperatures of 350 to 380 ° C in contact with the catalyst. 3. A process for the production of muscon according to claim 1, characterized in that that the 2,15-diketones of the general formula II with brings a TiO₂ catalyst into contact.   4. A process for the production of muscon according to claim 1, characterized in that that the 2,15-diketones of the general formula II with a TiO₂ catalyst doped with alkali or alkaline earth metal oxides brings in contact. 5. Open-chain 2-unsaturated 2,15-diketones of the general formula II CH₃-CO-X-CO-CH₃ (II) in the X for an unbranched alkadienylene radical of the structure stands. 6. A process for the preparation of a mixture of the 2-unsaturated 2,15-diketones of the formulas IIb and IIc according to claim 5 characterized in that 1,10-decanediol of the formula III oxidatively dehydrated,
the 1,10-decanedial of formula IV thus obtained a Wittig reaction with 2 moles of a 2-oxo-propenyl-triphenylphosphonium salt of the formula V wherein
Y⊖ stands for Cl⁻, Br⁻ or HSO₄⊖, subjects and distills the reaction product. 7. A process for the preparation of the 2-unsaturated 2,15-diketone of the formula IId according to claim 5 characterized in that one

• A. 1,6-hexane diol of formula VI oxidatively dehydrated,
• B. the resulting adipindialdehyde of formula VII with 2 mol of a vinyl magnesium halide of the formula VIIICH₂ = CH-Mg-Hal (VIII) in which Hal is Cl or Br, reacted in a Grignard reaction and
• C. the 1,9-decadiene-3,8-diol of the formula IX obtained in this way a Carroll reaction with an alkyl acetoacetate.

8. A process for the preparation of muscon according to claim 1, characterized in that an open-chain 2,15-diketone of the formulas IIa or IId in contact with the catalyst, which was prepared in the following manner:

• A. Oxidative dehydrogenation of 1,6-hexanediol of the formula VI
• B. Grignard reaction of the resulting adipindialdehyde of the formula VII with 2 moles each of a vinyl magnesium halide of the formula VIIICH₂ = CH-Mg-Hal (VIII) in which Hal is Cl or Br,
• C. Carroll reaction of the 1,9-decadiene-3,8-diol of the formula IX obtained in this way with an alkyl acetoacetate and
• D. optionally subsequent catalytic hydrogenation of the open-chain ketone of the formula IId obtained in this way.

9. A process for the preparation of muscon according to claim 1, characterized in that an open-chain 2,15-diketone of the formulas IIa or a mixture of the 2,15-diketones of the formulas IIb and IIc in contact with the catalyst, which was prepared in the following manner:

• A. Oxidative dehydrogenation of 1,10-decanediol of Formula III
• B. Wittig reaction of the resulting 1,10-decanediol of the formula IV with 2 moles each of a 2-oxo-propenyl-triphenylphosphonium salt of the formula V wherein
  Y⊖ stands for Cl⁻, Br⁻ or HSO₄⊖, and
• C. optionally subsequent catalytic hydrogenation of the resulting mixture of 2,5-diketones of the formulas IIb and IIc.

10. Use of the open-chain, double-unsaturated 2,15-diketones of the general formulas IIb, IIc and IId according to claim 5 as intermediates for the preparation of muscon of the formula I.